melphalan and Retinal-Artery-Occlusion

We describe the histopathologic findings in a nonhuman primate (NHP) model of superselective intraophthalmic artery chemotherapy (SSIOAC), detailing ocular and orbital vascular adverse effects.. To further document, using comprehensive ocular and orbital histopathology, previously reported toxic effects observed with real-time ophthalmoscopy during SSIOAC in a NHP model.. Comparative interventional case series.. Preclinical trial approved under the guidelines of the Institutional Animal Care and Utilization committee.. Six adult male rhesus macaques (Macacca mulatta).. The right eye of each NHP was treated with 3 cycles of SSIOAC using either melphalan (5 mg/30 mL) or carboplatin (30 mg/30 mL). Both eyes in each animal were enucleated 6 hours after the final procedure, before euthanasia and formalin perfusion of the NHP; we then performed orbital dissection of the arterial vasculature and optic nerves.. Histopathologic examination of the eyes, optic nerves, and orbital vessels of the 6 treated NHPs.. We found leukostasis with retinal arteriole occlusion in all treated eyes. Retinal endothelial cells stained positive for 2 inflammatory markers, intercellular adhesion molecule 1 and interleukin 8. Transmission electron microscopy revealed occlusion of the retinal vessels with ultrastructural changes in the endothelial cells and surrounding pericytes. Additional findings included nerve fiber layer infarcts, central retinal artery thrombosis, hypertrophy and occlusion of choroidal arteries with disruption of the internal elastic lamina, patchy choroidal inflammation, and birefringent intravascular foreign bodies. Orbital findings included ophthalmic artery and central retinal artery wall dissection, fracturing of the internal elastic lamina, intimal hyperplasia, and eyelid vessel damage. Optic nerves displayed hemorrhage, leukostasis, and foreign body crystallization. Control eyes, optic nerves, and orbital vessels were normal.. Histopathologic examination of our nonhuman primate model for SSIOAC revealed significant toxic effects in the ocular and orbital vasculature. These findings substantiate previous observations with real-time retinal imaging and parallel reported vascular toxic effects in children with retinoblastoma treated with SSIOAC.

Topics: Animals; Antineoplastic Agents, Alkylating; Arterioles; Biomarkers; Carboplatin; Choroiditis; Endothelium, Vascular; Immunoenzyme Techniques; Infusions, Intra-Arterial; Intercellular Adhesion Molecule-1; Interleukin-8; Leukostasis; Macaca mulatta; Male; Melphalan; Nerve Fibers; Ophthalmic Artery; Retinal Artery Occlusion; Retinal Ganglion Cells

Topics: Antineoplastic Agents, Alkylating; Electroretinography; Humans; Infant; Infusions, Intra-Arterial; Ischemia; Male; Melphalan; Ophthalmic Artery; Retina; Retinal Artery Occlusion; Retinal Neoplasms; Retinal Vein Occlusion; Retinoblastoma

Superselective ophthalmic artery chemotherapy (SOAC) has recently been proposed as an alternative to intravenous chemoreduction for advanced intraocular retinoblastoma. Preliminary results appear promising in terms of tumor control and eye conservation, but little is known regarding ocular toxicity and visual prognosis. In this study, we report on the vascular adverse effects observed in our initial cohort of 13 patients.. The charts of 13 consecutive patients with retinoblastoma who received a total of 30 injections (up to 3 injections of a single agent per patient at 3-week interval) of melphalan (0.35 mg/kg) in the ophthalmic artery between November 2008 and June 2010 were retrospectively reviewed. RetCam fundus photography and fluorescein angiography were performed at presentation and before each injection. Vision was assessed at the latest visit.. Enucleation and external beam radiotherapy could be avoided in all cases but one, with a mean follow-up of 7 months. Sectoral choroidal occlusive vasculopathy leading to chorioretinal atrophy was observed temporally in 2 eyes (15%) 3 weeks to 6 weeks after the beginning of SOAC and retinal arteriolar emboli in 1 eye 2 weeks after injection. There was no stroke or other clinically significant systemic side effects except a perioperative transient spasm of the internal carotid artery in one patient. Vision ranged between 20/1600 and 20/32 depending on the status of the macula.. Superselective ophthalmic artery chemotherapy was effective in all patients with no stroke or other systemic vascular complications. Unlike intravenous chemoreduction, SOAC is associated with potentially sight-threatening adverse effects, such as severe chorioretinal atrophy secondary to subacute choroidal occlusive vasculopathy or central retinal artery embolism, not to mention the risk of ophthalmic artery obstruction, which was not observed in this series. Further analysis of the risks and benefits of SOAC will define its role within the therapeutic arsenal. Meanwhile, we suggest that SOAC should be given in one eye only and restricted to advanced cases of retinoblastoma, as an alternative to enucleation and/or external beam radiotherapy.

Topics: Antineoplastic Agents, Alkylating; Atrophy; Chemotherapy, Cancer, Regional Perfusion; Child, Preschool; Choroid; Choroid Diseases; Fluorescein Angiography; Humans; Infant; Melphalan; Ophthalmic Artery; Photography; Retinal Artery Occlusion; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Visual Acuity

Topics: Antineoplastic Agents, Alkylating; Choroid Diseases; Humans; Melphalan; Ophthalmic Artery; Retinal Artery Occlusion; Retinal Neoplasms; Retinoblastoma